Lesson 21 -- Nicotine

What is the primary mechanism of action of nicotine?

is an agonist at nicotinic acetylcholine receptors (nAChRs) — ligand-gated ion channels that allow Na⁺ and Ca²⁺ influx, leading to depolarization and excitation

What brain circuit mediates nicotine reinforcement?

The mesolimbic dopamine pathway — nicotine stimulates nAChRs on VTA dopamine neurons and on glutamate terminals, increasing dopamine release in the nucleus accumbens → reward

What happens to high-affinity nAChRs (α4β2) after chronic nicotine exposure?

They undergo desensitization and upregulation — receptors become less responsive, but more numerous, contributing to tolerance and dependence

How does subunit composition affect nicotine affinity?

receptors with α4β2 have high affinity (activated by low nicotine), while α7 receptors have lower affinity but allow more Ca²⁺ influx — key for synaptic plasticity and learning effects

What are two behavioral models of nicotine dependence?

• Nicotine resource model: Smoking maintains nicotine levels for mood/cognitive benefits.

• Deprivation reversal model: Smoking relieves withdrawal symptoms, not provides added benefit.

What are key features of nicotine withdrawal?

Irritability, anxiety, trouble concentrating, insomnia, increased appetite (not weight loss)

Which nAChR subunits are critical for nicotine reinforcement?

α4 and β2 subunits in the VTA — knockout of these reduces nicotine’s rewarding effects

Which subunit is implicated in nicotine aversion?

α5 — activation of α5-containing receptors in the habenula–interpeduncular pathway produces aversive effects and limits intake

What pharmacotherapies help treat nicotine dependence?

• Nicotine replacement (patch, gum, inhaler)

• Varenicline: partial α4β2 agonist (reduces craving)

• Bupropion: blocks DA/NE reuptake, weak nAChR antagonist

What pharmacokinetic factors influence nicotine intake from smoking?

Inhalation depth, puff frequency, and metabolism rate (CYP2A6) determine how much nicotine reaches the brain (via lungs → heart → brain in ~7 seconds)

What type of drug is nicotine?

Nicotine is a stimulant and reinforcing psychoactive substance that acts as an agonist at nicotinic acetylcholine receptors (nAChRs)

Where is nicotine naturally found?

In tobacco leaves (Nicotiana tabacum). It’s the primary addictive compound in tobacco products

What type of receptor does nicotine act on?

Nicotinic acetylcholine receptors (nAChRs) — these are ligand-gated ion channels (ionotropic receptors)

What happens when nicotine binds to an nAChR?

The channel opens, allowing Na⁺ and Ca²⁺ ions to enter the neuron → depolarization → increased neuronal excitability and neurotransmitter release

Where are nAChRs located in the brain?

Abundantly in the Ventral Tegmental Area (VTA), nucleus accumbens (NAc), prefrontal cortex, and hippocampus

How does nicotine activate the reward pathway?

Nicotine binds to nAChRs on dopaminergic neurons in the VTA, increasing dopamine release in the NAc, producing reinforcement and pleasure

What other neurotransmitters are affected by nicotine?

• Dopamine → reward, pleasure

• Acetylcholine → alertness, attention

• Glutamate → learning, memory

• Norepinephrine → arousal

• GABA → inhibitory control (but reduced with chronic use)

Does Nicotine act as both a stimulant and a relaxant?

Yes, nicotine can stimulate alertness and focus; with chronic use, desensitized receptors can produce a calming effect due to reduced firing

What happens to nAChRs after chronic nicotine exposure?

They undergo desensitization (temporary inactivation) and upregulation (increase in receptor number) as the brain compensates for overstimulation

Why does tolerance develop to nicotine’s effects?

Because repeated receptor activation leads to receptor desensitization and altered receptor sensitivity, requiring higher doses for the same effect

What happens during nicotine withdrawal?

• ↓ Dopamine release in the reward system → anhedonia, irritability

• ↑ CRF (corticotropin-releasing factor) in the amygdala → stress, anxiety

• Physical symptoms: craving, restlessness, poor concentration, insomnia

How quickly does nicotine reach the brain after inhalation?

Within 7–10 seconds, almost as fast as intravenous injection

What is nicotine’s half-life in the body?

Around 2 hours, though this can vary depending on genetics and metabolism

What enzyme metabolizes nicotine?

CYP2A6 in the liver, converting it into cotinine, the main metabolite used as a biomarker for nicotine exposure

What are nicotine’s short-term effects?

• ↑ Heart rate and blood pressure

• ↑ Alertness and attention

• ↓ Appetite

• Mild euphoria and relaxation

What are the long-term health consequences of nicotine and tobacco use?

• Cardiovascular disease (hypertension, atherosclerosis)

• Lung cancer and COPD (due to tar and other toxins, not nicotine itself)

• Addiction and dependence

Nicotine itself is the main carcinogen in tobacco?

No, nicotine is addictive, but tar, carbon monoxide, and other chemicals in tobacco smoke are the primary carcinogens

What are some pharmacological aids for nicotine addiction?

• Nicotine replacement therapy (patch, gum, lozenge) → reduces withdrawal

• Bupropion (Zyban) → blocks dopamine/norepinephrine reuptake

• Varenicline (Chantix) → partial agonist at α4β2 nAChRs (reduces cravings and blocks reward from smoking)

How does varenicline (Chantix) work?

It partially activates α4β2 nAChRs to reduce cravings while blocking nicotine from fully stimulating the receptors — easing withdrawal without full reward

Nicotine withdrawal symptoms include

• Anxiety and irritability

• Difficulty concentrating

• Cravings and restlessness

• Depressed mood

• Weight gain (due to increased appetite)

What makes nicotine addiction so persistent?

• Rapid delivery of nicotine to the brain

• Conditioned cues (smoking contexts, sensory triggers)

• Short half-life, causing frequent craving cycles

• Strong reinforcement via dopamine systemv